Mesenchymal Cell Implantation
Implantation of mesenchymal stromal cells (MSCs) and their derivatives is being developed as a treatment for various degenerative disorders of the central nervous system (CNS). The therapeutic effects resulting from MSC implantation into the CNS are thought to be due primarily to the secretion of soluble factors from living implanted cells, which provide tissue protective, regenerative, and immunomodulatory stimuli [1-3]. Paradoxically, however, the engraftment rate of MSCs in the CNS subsequent to implantation is low [4,5]; and therapeutic benefits have been observed to continue long after the grafted cells can no longer be detected. A variety of explanations have been proposed to account for the poor engraftment of implanted MSCs. Some investigators suggest the triggering of innate, and subsequent adaptive, immune responses to explain graft loss; however, others find similar rates of graft cell loss irrespective of HLA matching status [6,7]. Additional studies have provided evidence that allogeneic MSCs do not elicit a significant immune response after implantation (reviewed in [8]). It has also been reported that intracellularly labeled MSCs (either alive or dead), implanted into the adult brain, can transfer labels to surrounding and distant cells of the recipient, and the labels can become incorporated into cells of the recipient [9,10].
FGF-2
FGF2 (also known as basic fibroblast growth factor, or bFGF) is a major growth factor for stem cells, a potent inducer of angiogenesis, an essential wound healing mediator, and a major player in the development and regeneration of the nervous system (reviewed in [11]). Five FGF2 isoforms are translated from a unique FGF2 mRNA by alternative translation initiation: an 18 kD low molecular weight (LMW) isoform; and high molecular weight (HMW) isoforms comprising molecular weights of 22, 22.5, 24, and 34 kD. LMW FGF2 is mostly cytoplasmic and is secreted, while the HMW isoforms are predominantly nuclear, however any of the isoforms can be found in the nucleus, cytoplasm, or extracellular matrix under certain conditions. All isoforms lack a signal peptide to direct secretion through the endoplasmic reticulum-Golgi pathway. Early studies demonstrated that mechanically wounded monolayers of endothelial cells release high levels of FGF2 [12, 13]. Based on these studies and the lack of signal peptide for secretion, cell death or even sub-lethal injury have been described as a major mechanism for FGF2 release [14]. Accordingly, FGF2 has been nominated as a “wound hormone for rapidly initiating the cell growth required for routine maintenance of tissue integrity and/or repair after injury” [15].
While many reports document the expression of FGF2 mRNA by MSCs and demonstrate the presence of intracellular FGF2 protein [11, 12, 16], very few reports provide measurements of FGF2 secretion, because the concentration of secreted FGF2 is very low [17, 18]. Perhaps for this reason, FGF2 has not been considered to be a primary candidate for mediating the regenerative effects of implanted MSC on surrounding neural tissue.
DNTT-MSCs
DNTT-MSCs (“descendants of NICD transiently-transfected MSCs”) are a population of cells that can be derived from human bone marrow MSCs by transient transfection of MSCs with a vector encoding the Notch intracellular domain (NICD); e.g., the human Notch1 intracellular domain (NICD1), followed by selection and subsequent expansion. This process produces a cell population that demonstrates superior angiogenic and neuropoietic (i.e., growth and differentiation of neural precursor cells) properties in vitro, compared to the parental MSCs [19-21]. The neuropoietic effects of DNTT-MSCs have been attributed to the increased expression, and correspondingly, increased secretion, of FGF1, FGF2, and BMPs [19, 22].
However, very low levels of FGF2 are secreted by MSCs or DNTT-MSCs. Tate et al. (2010) Cell Transplantation 19: 973-984. Accordingly, if FGF2 is responsible, in whole or in part, for the neuropoietic effects of MSCs and/or DNTT-MSCs, its source remains elusive.